Idiopathic pulmonary fibrosis (IPF) is a fatal disease for which current therapies have failed. Preventing alveolar epithelial cell (AEC) injury and myofibroblast (MF) activation/survival in distal airways may slow progression of fibrosis and enhance survival. Recent evidence from in vitro studies, in vivo models of pulmonary fibrosis, and previous clinical trials indicate that agents that block either growth factor production or fibroblast survival may attenuate fibrosis. Pirfenidone and interferon-gamma (IFN-?) may down-regulate both AEC apoptosis and fibroblast survival, HMGCoA reductase inhibitors (lovastatin) down-regulate fibroblast survival and 5-lipoxygenase activating protein (FLAP) inhibitors (MK-0591) down-regulate fibroblast-generated extracellular matrix production. We hypothesize that these agents have the potential to improve survival and slow disease progression in patients with IPF. To address this, we propose the following specific aims: Specific Aim 1: Determine if down-regulating growth factor production in distal airways via treatment with the combination of pirfenidone and IFN-?-lb improves survival over two years in patients with IPF. We hypothesize that the combination of these two agents will decrease mortality and slow disease progression to a greater extent than pirfenidone agent alone. To test this, we will conduct a multi-center, randomized, double-blind, placebo-controlled, stratified, parallel group two-year study of clinical effect of pirfenidone and IFN?-1b compared with pirfenidone alone or placebo in a large cohort of patients with IPF. Specific Aim 2: Determine if down-regulating fibroblast survival and matrix protein production with the combination of lovastatin and MK-0591 improves survival over two years in patients with IPF. We hypothesize that the combination of these two agents will decrease mortality and slow disease progression to a greater extent than either agent alone. To test this, we will conduct a multi-center, randomized, double-blind, placebo-controlled, stratified, parallel group two-year study of clinical effect of lovastatin and MK-0591 compared with either agent alone or placebo in a large cohort of patients with IPF. These clinical trials will establish whether agents that modulate interactions between AECs and fibroblasts, and thus reduce fibrosis and sequential damage in distal airways, can reduce mortality and slow disease progression in IPF. (End of Abstract)